The protein kinases represent an important family of proteins involved in the regulation of key cellular processes, violation of activity of which can lead to oncological, chronic inflammatory diseases, diseases of the central nervous system, etc. The list of kinases, the therapeutic significance of which to date has preclinical or clinical validation, includes: ABL1, ALK, AKT, AKT2, AURKA, BRAF, BCR-ABL, BLK, BRK, C-KIT, C-MET, C-SRC, CAMK2B, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CRAF1, CHEK1, CHEK2, CLK1, CLK3, CSF1R, CSK, CSNK1G2, CSNK1G3, CSNK2A1, DAPK1, DAPK2, DAPK3, EGFR, EPHA2, EPHA3, EPHA5, ERBB2, ERBB3, ERBB4, ERK, ERK2, ERK3, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGR, FLT-1, FYN, GSK3B, HCK, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KIT, LCK, LOK, MAP3K5, MAPKAPK2, MARK1, MEK1, MEK2, MET, MKNK2, MST1, NEK2, P38α, P38δ, P38γ, PAK1, PAK4, PAK6, PAK7, PDPK1, PDGFR, PIK3CG, PIM1, PIM2, PKC, PLK1, PLK4, PRKCQ, PRKR, PTK2, PTK2B, RET, ROCK1, ROS1, RPS6KA1, SLK, SRC, SRPK1, STK16, SYK, TAK1, TGFBR1, TIE, TIE2, TNK2, TRK, VEGFR2, WEE1, ZAP70 (Karaman, M. W. et. al., Nat Biotechnol, 2008, 26, 127-32; Bhagwat, S. S., Purinergic Signal, 2009, 5, 107-15). This list is constantly growing with the advent of new experimental data.
The promising approach for the treatment of diseases associated with the abberant activity of protein kinases includes the use of low-molecular chemical compounds for the inhibition of their activity. Examples of such inhibitors approved for use in clinical practice, are: Imatinib, Nilotinib, Dasatinib, Sunitinib, Sorafenib, Lapatinib, Gefitinib, Erlotinib, Crizotinib. A large number of drug candidate kinase inhibitors are currently at the stage of clinical trials and preclinical development.
Anaplastic Lymphoma Kinase, ALK—is a transmembrane receptor tyrosine kinase that belongs to the family of insulin receptors. ALK kinase is most strongly expressed in the brain of the newborn, suggesting a possible role of ALK in brain development (Duyster, J. et. al., Oncogene, 2001, 20, 5623-37).
Aberrant activity of Anaplastic Lymphoma Kinase is a cause of many oncological diseases. For example, the cause of 3-6% of non-small cell lung cancer (NSCLC) is chromosomal translocation activating the formation of a chimeric protein consisting of the EML4 protein and ALK intracellular domain (Pao, W. et. al., Lancet Oncol, 2011, 12, 175-80; Shaw, A. T. et. al., Clin Cancer Res, 2011, 17, 2081-6). Other chromosomal translocation leads to the formation of the NPM-ALK chimeric protein, and causes about 60% of the cases of anaplastic large cell lymphoma (ALCL) (Kutok, J. L. et. al., J Clin Oncol, 2002, 20, 3691-702). Constitutive tyrosine kinase activity of the chimeric proteins, EML4-ALK in the case of NSCLC, or NPM-ALK in the case of ALCL, causes activation of downstream signaling pathways responsible for the cell division and protection from apoptosis and eventually leading to cell oncotransformation (Falini, B. et. al., Blood, 1999, 94, 3509-15; Morris, S. W. et. al., Br J Haematol, 2001, 113, 275-95; Bai, R. Y. et. al., Blood, 2000, 96, 4319-27). ALK-positive carcinomata are oncogene-dependent: blocking the enzyme activity using ALK inhibitors leads to cell cycle arrest and apoptosis of cancer cells (Christensen, J. G. et. al., Mol Cancer Ther, 2007, 6, 3314-22).
The ALK inhibition is a promising strategy to combat ALK-positive forms of non-small cell lung cancer, anaplastic large cell lymphoma, and other oncological diseases, the cause of which lies in a constitutive activity of ALK. Clinical trials of ALK inhibitor Crizotinib in patients with advanced NSCLC showed that the life expectancy of patients increased by 9 months and more (Di Maio, M. et. al., J Clin Oncol, 2009, 27, 1836-43) even to 2 years (Kwak, E. L. et. al., N Engl J Med, 2010, 363, 1693-703). To date there are numerous known ALK inhibitors, including indazole isoquinolines (WO 2005/009389), thiazole and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005/080393), pyrimidinediamines (WO 2005/016894), aminopyridines and aminopyrazines (WO 2004/076412; WO 2007/066187), piridopyrazines (WO 2007/130468).
The use of low-molecular inhibitors of ALK in therapeutic practice has revealed a number of serious problems with their efficiency. Firstly, the problems are associated with low activity of inhibitors toward ALK mutated forms, which may eventually appear in patients. For example, it is known that the kinase domain of the EML4-ALK gene product, the target of non-small cell lung cancer, is susceptible to occurrence of mutations that determine resistance to Crizotinib (mutations L1196M, C1156Y, G1269A and F1174L) (Choi, Y. L. et. al., N Engl J Med, 2010, 363, 1734-9; Sasaki, T. et. al., Cancer Res, 2010, 70, 10038-43). The frequency of such mutations reaches 30% (Doebele, R. C. et. al., Clin Cancer Res, 2012). Secondly, increase in life expectancy of patients promotes the likelihood of brain metastases formation: on an average metastases occur in 50% of patients for 2 years of treatment (Shaw, A. T. et. al., Lancet Oncol, 2011, 12, 1004-12). Practically Crizotinib does not penetrate through the blood-brain barrier and therefore does not affect the brain metastases despite the fact that the primary tumor in the lung of the same patient may continue to decline (Costa, D. B. et. al., J Clin Oncol, 2011, 29, e443-5). Thus, development of new compounds capable of inhibiting the kinase mutant forms, and of penetrating through the blood-brain barrier is practically very important task.
This invention relates to new families of chemical compounds having increased efficacy in the inhibition of protein kinases and their mutants, and promising for use in the treatment of oncological, chronic inflammatory and other diseases.